ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT2 domain with γH2AX

Robert A. Baldock; Matthew Day; Oliver J. Wilkinson; Ross Cloney; Penelope A. Jeggo; Antony W. Oliver; Felicity Z. Watts; Laurence H. Pearl

doi:10.1016/j.celrep.2015.10.074

ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT₂ domain with γH2AX

Robert A. Baldock, Matthew Day, Oliver J. Wilkinson, Ross Cloney, Penelope A. Jeggo, Antony W. Oliver, Felicity Z. Watts, Laurence H. Pearl

School of Pharmacy & Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT₂ domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications--H4K20me2 and H2AK13/K15ub--downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT₂ domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1.

Original language	English
Pages (from-to)	2081-2089
Number of pages	9
Journal	Cell Reports
Volume	13
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2015.10.074
Publication status	Published - 15 Dec 2015

Keywords

animals
ataxia telangiectasia mutated proteins/metabolism
chromosomal proteins, non-histone/metabolism
crystallography, X-Ray
DNA breaks, double-stranded
DNA repair/physiology
DNA-binding proteins/metabolism
fluorescent antibody technique
gene knockdown techniques
heterochromatin/metabolism
histones/metabolism
humans
Intracellular Signaling Peptides and Proteins/metabolism
mice
protein processing, post-translational
protein structure, quaternary
RNA, small interfering
transfection
tumor suppressor p53-binding protein 1

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10.1016/j.celrep.2015.10.074

1-s2.0-S2211124715012826-mainFinal published version, 3.14 MBLicence: CC BY-NC-ND

Cite this

@article{6fc2b3f1832b41ce890d839c97b03907,

title = "ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT2 domain with γH2AX",

abstract = "53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications--H4K20me2 and H2AK13/K15ub--downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1.",

keywords = "animals, ataxia telangiectasia mutated proteins/metabolism, chromosomal proteins, non-histone/metabolism, crystallography, X-Ray, DNA breaks, double-stranded, DNA repair/physiology, DNA-binding proteins/metabolism, fluorescent antibody technique, gene knockdown techniques, heterochromatin/metabolism, histones/metabolism, humans, Intracellular Signaling Peptides and Proteins/metabolism, mice, protein processing, post-translational, protein structure, quaternary, RNA, small interfering, transfection, tumor suppressor p53-binding protein 1",

author = "Baldock, {Robert A.} and Matthew Day and Wilkinson, {Oliver J.} and Ross Cloney and Jeggo, {Penelope A.} and Oliver, {Antony W.} and Watts, {Felicity Z.} and Pearl, {Laurence H.}",

year = "2015",

month = dec,

day = "15",

doi = "10.1016/j.celrep.2015.10.074",

language = "English",

volume = "13",

pages = "2081--2089",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "10",

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TY - JOUR

T1 - ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT2 domain with γH2AX

AU - Baldock, Robert A.

AU - Day, Matthew

AU - Wilkinson, Oliver J.

AU - Cloney, Ross

AU - Jeggo, Penelope A.

AU - Oliver, Antony W.

AU - Watts, Felicity Z.

AU - Pearl, Laurence H.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications--H4K20me2 and H2AK13/K15ub--downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1.

AB - 53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications--H4K20me2 and H2AK13/K15ub--downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1.

KW - animals

KW - ataxia telangiectasia mutated proteins/metabolism

KW - chromosomal proteins, non-histone/metabolism

KW - crystallography, X-Ray

KW - DNA breaks, double-stranded

KW - DNA repair/physiology

KW - DNA-binding proteins/metabolism

KW - fluorescent antibody technique

KW - gene knockdown techniques

KW - heterochromatin/metabolism

KW - histones/metabolism

KW - humans

KW - Intracellular Signaling Peptides and Proteins/metabolism

KW - mice

KW - protein processing, post-translational

KW - protein structure, quaternary

KW - RNA, small interfering

KW - transfection

KW - tumor suppressor p53-binding protein 1

U2 - 10.1016/j.celrep.2015.10.074

DO - 10.1016/j.celrep.2015.10.074

M3 - Article

C2 - 26628370

SN - 2211-1247

VL - 13

SP - 2081

EP - 2089

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT2 domain with γH2AX

Abstract

Keywords

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ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT₂ domain with γH2AX